基于核受体PXR、CAR调控CYP3A4研究三七总皂苷提高硝苯地平疗效的机制

Mechanism of Panax notoginseng saponins improving the efficacy of nifedipine based on nuclear receptor PXR and CAR regulation CYP3A4

目的 研究三七总皂苷(PNS)与硝苯地平(NF)联用后疗效增强的作用机制,为指导临床合理用药提供理论遵循。方法 将SD雄性大鼠随机分为空白组、三七总皂苷组、硝苯地平组和联合给药组。采用HPLC测定血浆中硝苯地平及肝微粒体中咪达唑仑的浓度;应用qPCR技术检测核受体PXR、CAR和肝药代谢酶CYP3A4的基因表达量。结果 与NF组相比,PNS+NF组中硝苯地平药时曲线下面积升高、半衰期延长、清除率降低、最大血药浓度Cmax和达峰时间t_(max)增加(P<0.01);与空白组相比,PNS组与PNS+NF组中肝脏药物代谢酶CYP3A4活性降低(P<0.05),PNS组与PNS+NF组肝脏中核受体PXR、CAR和CYP3A4m RNA表达量均降低(P<0.01);与NF组相比,PNS组与PNS+NF组肝脏中核受体PXR、CAR和CYP3A4 mRNA表达量均降低,但差异无统计学意义。结论 三七总皂苷与硝苯地平联用后,PNS可能通过抑制核受体PXR、CAR进而抑制肝药代谢酶CYP3A4的活性与基因表达,提高硝苯地平血药浓度使疗效增强。

Objective To determine the mechanism of synergistic effect of Panax notoginseng saponins(PNS)and nifedipine(NF)to provide a theoretical basis for its rational use.Methods SD male rats were randomly divided into a blank group,a PNS group,a NF group and a co-administration group.The concentrations of nifedipine in the plasma and midazolam in the liver microsomes were determined by HPLC.The gene expression levels of nuclear receptor PXR,CAR and liver drug metabolizing enzyme CYP3A4 were determined by qPCR.Results Compared with the NF group,the area under the concentration-time curve of nifedipine was increased,the half-life was prolonged,the clearance rate was decreased,the maximum plasma concentration and time to the peak were increased in the co-administration group(P<0.01).Compared with the blank group,the activity of liver drug metabolizing enzyme CYP3A4 in the PNS group and the co-administration group decreased(P<0.05),and the expression of nuclear receptor PXR,CAR and CYP3A4 mRNA in the liver of the PNS group and the co-administration group also decreased(P<0.01).Compared with the NF group,the expressions of PXR,CAR and CYP3A4 mRNA in the liver of the PNS group and the co-administration group decreased,without much difference.Conclusion After combining Panax notoginseng saponins with nifedipine, PNS may inhibit the activity and gene expression of hepatic drug metabolizing enzyme CYP3A4 by inhibiting the nuclear receptors PXR and CAR, and increasing the plasma concentration of nifedipine to enhance the therapeutic effect.